The mammary ductal tree is comprised of stem cells, progenitor cells, and more differentiated epithelial and myoepithelial cells. Stem and progenitor cells are increasingly thought to be the primary targets of tumorigenesis, and indeed mammary tumors initiated by oncogenes such as Wnt-1 contain a mix of cell types implying that they arose from multipotent progenitors. However, tumors initiated by other important oncogenes such as ErbB2 usually do not contain mixed cell types, suggesting that they might originate from transformation of more differentiated cells. Furthermore, these tumors differ in their estrogen receptor status, so that the dependence on estrogen for tumor development may also differ. To test rigorously whether different oncogenes induce tumors preferentially from different mammary cell differentiation states, we use the avian retrovirus (RCAS) somatic gene transfer technique to target cells transgenically engingeered to express the gene encoding the RCAS receptor TVA - we were the first to adapt this technique to the mammary gland, and have already developed several mouse strains expressing tva from different mammary cell types and differentiation stages and begun to study tumor formation induced in these strains by several oncogenes carried by RCAS. Our preliminary data strongly suggest the hypothesis that different oncogenes do indeed prefer to induce tumors from different cell types and differentiation states in the mammary gland. Because understanding different paths to breast cancer evolution at both molecular and cellular levels could be critical for devising early prevention strategies, we propose here to use our uniquely suited models to: (1) determine whether differentiated mammary cells are more susceptible than progenitor cells (defined by new, more selective promoters) to tumor induction by ErbB2, and whether this susceptibility is due to the failure of the more differentiated cells to erect an oncogenic barrier involving the DNA damage response; (2) investigate whether mammary progenitor cells are more susceptible to induction of early lesions and tumors by Wnt-1, and what molecular network in the progenitor cells is preferentially activated by Wnt signaling to accelerate tumor development; and (3) determine how estrogen (or estrogen deprivation) affects tumor evolution induced by ErbB2 vs. Wnt in differentiated vs. progenitor cells, and which molecular mechanisms are involved in this estrogen dependence.